This invention relates to allylamine-containing liposomes, i.e. liposomes loaded with an allylamine compound as the pharmacologically active agent.
The present invention provides in an aspect liposomes comprising a compound of formula I 
The compound of formula I may be used e.g. in free form or in acid addition salt form. An acid addition salt form may be prepared from the free base form in conventional manner and vice-versa. Examples of suitable acid addition salt forms are the hydrochloride, the lactate and the ascorbate.
The compound of formula I is known from e.g. BE-PS-853xe2x80x2976 and EP-A-24xe2x80x2587. It belongs to the class of allylamine anti-mycotics. It is acknowledged in the art under its generic name terbinafine and is commercially available under the tradename LAMISIL. While terbinafine is highly active upon both topical and oral administration, in vitro serum can antagonize to some extent its antifungal activity.
It is thus desirable to find a drug delivery system which can improve the bioavailability of the compound of formula I in order to overcome serum binding and/or favourably influence parameters such as pharmacokinetics and tissue distribution and/or reduce side effects and toxicity. Reduction of side effects and toxicity with maintenance or increase in the activity and therapeutic efficacy of the drug substance is pursued.
A promising approach meeting the above-mentioned criteria has now been found in the form of liposomes comprising the compound of formula I as the active agent. Thus pharmaceutically acceptable e.g. parenteral dosage form for the lipophilic compound of formula I has been obtained by means of liposomal preparations. No surface active agents (tensides) are required thereby and additional side effect problems commonly associated with their use are thus avoided.
A pulmonary application of liposomes comprising the compound of formula I e.g. by metered dose inhaler (MDI), aqueous or powder aerosol may lead to an immediate or sustained release of compound of formula I, depending on the liposomal composition, to produce the antifungal activity. A topical application of liposomes containing the compound of formula I may lead to enhanced accumulation of the drug at the site of administration, in turn leading to enhanced efficacy of the compound of formula I compared to non-liposomal application forms. On pulmonal application the liposomes comprising the compound of formula I are effective against fungal diseases of the lung such as candidiasis and various types of aspergillosis, e.g. infections by Aspergillus fumigatus and non-fumigatus Aspergilli.
An application by injection of liposomes according to the invention may lead to improved efficacy of the active agent in comparison to the same amount of the same agent when injected in a conventional injectable form. On the other hand equivalent efficacy of the compound of formula I may be achieved with a smaller amount of the active agent, when administered in form of liposomes carrying the compound of formula I. A substantial reduction of the required amount of the compound of formula I for treating a fungal disease may be achieved in this way.
Liposomes are lipid vesicles which are formed on addition of an aqueous solution to a dry film of phospholipids, e.g. if necessary with the addition of energy, or even to a certain extent spontaneously. The lipid most widely used is phosphatidylcholine. Altering the lipid composition, size, charge and membrane fluidity of the liposomes can greatly influence their distribution in the body. Drug molecules can either be encapsulated in the aqueous space or intercalated into the bilayer. In the last two decades liposomes have been applied to a variety of drugs but also to genetic material, enzymes and other (macro)molecules as delivery vehicles into living cells and other hydrophobic barriers in pharmacology, medicine, genetic engineering and in the cosmetic and food industries. In the treatment of systemic fungal infections these vesicles have also been successfully used as carriers of Amphotericin B and of nystatine.